Interferon-γ couples CD8 + T cell avidity and differentiation during infection

• Published in: Nature communications Vol. 14; no. 1; p. 6727
• Main Authors: Uhl, Lion F K, Cai, Han, Oram, Sophia L, Mahale, Jagdish N, MacLean, Andrew J, Mazet, Julie M, Piccirilli, Theo, He, Alexander J, Lau, Doreen, Elliott, Tim, Gerard, Audrey
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.10.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Antigens; Avidity; CD8 antigen; CD8-Positive T-Lymphocytes; Cell differentiation; Cell Differentiation - genetics; Cytokines; Differentiation; Effector cells; Immunological memory; Immunoregulation; Interferon-gamma - genetics; Lymphocytes; Lymphocytes T; Memory cells; Peptides; Phenotypes; Virtual memory systems; Viruses; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42455-4

Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8 T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.